| Eligibility |
Inclusion Criteria:
Participants are eligible to be included in the study only if ALL of the following criteria
apply:
1. Capable of giving signed informed consent as described in Appendix 3, which includes
compliance with the requirements and restrictions listed in the informed consent form
and in this protocol
2. Age =18 and =80 years
3. Patients with a confirmed diagnosis of AATD: Pi*ZZ, Pi*SZ, Pi*null, or another rare
phenotype/genotype known to be associated with either low (serum AAT level <11 µM or
<57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.
4. FEV1 =25% predicted
5. Patients will be eligible if they are either a) are not currently receiving
augmentation treatment and have not received augmentation in the 12 weeks prior to
screening or b) have received weekly infusions of augmentation at 60 mg/kg for at
least 12 weeks prior to screening and intend to continue augmentation through the
study period.
6. Male or female sex a. Male participants must agree to use a highly effective
contraception as detailed in Appendix 5 during the treatment period and for at least 4
days after the last dose of study treatment and refrain from donating sperm during
this period b. Female participants are eligible to participate if not pregnant; not
breastfeeding; and at least one of the following conditions is met: i. Not a woman of
childbearing potential as defined in Appendix 5 OR ii. A woman of childbearing
potential who agrees to follow the contraceptive guidance in Appendix 5. During the
treatment phase and for at least 4 days after the last dose of study medication.
Exclusion Criteria:
Participants are excluded from the study if ANY of the following criteria apply:
Excluded Medical Conditions
1. Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not known
to be independently associated with emphysema.
2. Any clinically diagnosed lung disease other than COPD such as diffuse interstitial
lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined
by the Investigator
3. Acute exacerbation of underlying lung disease requiring oral steroids and/or
antibiotics within 4 weeks of baseline
4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies,
including hepatitis B and C antibody)
5. HIV infection or other immunodeficiency or with an absolute neutrophil count =1.0 ×
109/L
6. Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase,
gamma-glutamyl transferase) >1.5 × upper limit of normal or total bilirubin > upper
limit of normal (unless Gilbert's disease with normal conjugated bilirubin)
7. Any of the following laboratory abnormalities are present at baseline:
1. Platelet count <150×109/L
2. Serum albumin = 3.5 g/dL
3. INR =1.2
4. CPK = ULN.
8. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices,
ascites or hepatic encephalopathy.
9. Evidence of other forms of chronic liver disease based on diagnostic testing as per
the guidelines (i.e. autoimmune liver disease, primary biliary cirrhosis, primary
sclerosing cholangitis, Wilson's disease, Hemochromatosis or iron overload).
10. Patients with nonalcoholic fatty liver disease (NAFLD) as diagnosed by any imaging
modality (or use of drugs associated with NAFLD for more than 2 weeks in the year
prior to screening).
11. Subjects with a history of significant alcohol consumption for a period of more than 3
consecutive months within 1 year prior to screening, defined as average of >20g/ day
in female subjects and >30g/ day in male subjects.
12. Fibrosis-4 (FIB-4) score >3.25
13. Any of the following cardiovascular conditions within 6 months prior to the screening
visit:
1. Myocardial infarction or unstable angina
2. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary
intervention, or carotid revascularization procedure
3. Uncontrolled hypertension
4. Stroke or transient ischemic attack
14. Congestive heart failure (New York Heart Association III/IV) with left ventricular
ejection fraction < 40%
15. Any clinically significant 12-lead electrocardiogram abnormalities at screening or
baseline, including corrected QT interval by Fridericia's correction method >450 ms or
history of significant cardiac dysrhythmia, including long QT syndrome
16. History of cancer within the last 5 years, except for well-treated basal cell
carcinoma and squamous cell carcinoma of the skin
17. Other documented comorbidities or laboratory abnormalities that in the opinion of the
Investigator could affect the outcome of the study assessments, participant safety, or
ability of the participant to comply with the requirements of the protocol
Excluded Prior/Concomitant Therapy
18. Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable
or higher equivalent dose, or use of other immunosuppressant therapies are prohibited
19. Immunomodulating monoclonal antibodies within 6 months prior to screening are
prohibited
20. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited. Daily use
of acetaminophen up to 2 g per day and aspirin up to 325 mg per day is permitted.
21. Initiation of drugs known for hepatotoxic potential within the 28 days prior to
screening including but not limited to: statins, NSAIDS, amoxicillin/clavulanate, PDE
inhibitors (theophylline, roflumilast), and anti-epileptics. Subjects on established
treatment for more than 28 days prior to screening will not be excluded. Requirement
for medications mainly metabolized by CYP2C9 and with narrow therapeutic index (eg,
warfarin, phenytoin) is prohibited
Excluded Prior/Concurrent Clinical Study Experience
22. Participation in any clinical investigation using medical devices or non-biologic
treatments within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to
the initial dosing (or longer if required by local regulations) is prohibited
23. Participation in any clinical investigation using biologic treatment within 6 months
of screening is prohibited
24. Previous participation in a gene therapy study for AATD at any time is prohibited
Other Exclusions
25. History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the
class of neutrophil elastase inhibitors
26. Known hypersensitivity to medications used in the study procedures (e.g. midazolam,
fentanyl, and lidocaine for bronchoscopy)
|
